Role of Innate Immunity and Microbiome in the Inflammation of Aging and Long-Term Antiretroviral Therapy Summary Inflammaging, characteristic of persistent systemic inflammation in the aging population, has been linked to frailty syndrome with increased risk of cardiovascular disease, impaired mobility, cancer, cognitive decline, and immunosenescence. Similarities between inflammaging and the course of treated HIV infections, including chronic inflammation associated with gut epithelial barrier damage and microbial translocation, suggest that HIV infection compresses the aging process, accelerating the development of comorbidities and frailty. Type- 17 immune cells that express the transcription factor ROR?t and type-17 cytokines (IL17A, IL22, etc.) are critical for a healthy gut barrier function and maintenance of mucosal immune and microbial homeostasis, and function by stimulating neutrophil recruitment, epithelial cell proliferation, production of tight junction proteins and anti-microbial defensins. Others and we have found that innate CD161+ T cells are a potent source of IL- 17 and are enriched in the gut mucosa. The first goal of this study is to determine the relationship of systemic inflammation with the functions of innate type-17 immune cells (including innate T cells and innate lymphoid cells) and the gut microbial composition. Utilizing the rhesus macaque model that most closely resembles human aging as well as HIV-AIDS, it will be examined whether plasma biomarkers of inflammation are associated with the immune signature of innate type-17 cells and fecal microbiome in aging vs. young adult macaques. This will help describe an inflammaging phenotype based on inflammation-associated gut mucosal immune signature and microbiome of aging macaques. The second goal is to establish whether long-term ART in young adult macaques with or without SIV infection leads to inflammaging-associated perturbations in gut mucosal innate type-17 immunity and microbiome. This will establish whether similar or synergistic immune mechanisms of perturbations in gut mucosal homeostasis contribute to the phenomenon of accelerated aging in treated HIV infections and determine the factors associated with the inflammaging phenotype in long-term ART. These studies are relevant because they focus on understanding the immune mechanisms underlying inflammaging and HIV/ART-associated inflammation and whether HIV/ART-associated inflammation is accelerating the inflammaging process. The results of this study will provide valuable insights into the role of gut mucosal type-17 cells and its microbiome in local and systemic inflammation of aging and ART. This will open new avenues to explore the development of applications aimed at modulating mucosal innate immune cells along with probiotics to reduce inflammaging and the risk of frailty syndrome in aging and treated HIV infections.